Anticholinergic drugs and dementia risk: Using stem cell-based studies to complement pharmacoepidemiology

Anticholinergic (AC) use remains common in older adults despite evidence of safety risks, including increased risk in dementia. Pharmacoepidemiology studies from various populations report associations between specific anticholinergic classes - antidepressants and bladder antimuscarinics - and increased dementia incidence. However, it is difficult to determine whether these associations are directly caused by the neurotoxic effects of anticholinergic drugs or by the underlying health conditions which the medications are taken for, known as confounding by indication. Here, we leverage human induced pluripotent stem cells-derived-neurons (hiPSC-Ns) to complement the pharmacoepidemiology studies by directly examining the effects of various anticholinergic classes on dementia-related cellular phenotypes.

These results corroborate population-based studies and suggest a molecular basis for the differences in dementia risk observed according to AC class. This warrants future work examining the effect of AC medications on hiPSC-derived cells from multiple subjects and examining other molecular outcomes including synaptic function and neuroinflammation in hiPSC-based models. Highlights: Certain classes of anticholinergic (AC) medications are linked to dementia.Human-induced pluripotent stem cell (hiPSC) models are used to directly test the cytotoxicity of AC medications.AC classes that are associated with dementia are more neurotoxic.

We treated human induced pluripotent stem cell (hiPSC)-derived neurons with eight drugs representing different AC medication classes, including antidepressants, bladder antimuscarinics, antihistamines, and antispasmodics. We analyzed these neurons for cytotoxicity, amyloid beta (Aβ) peptide levels in the conditioned medium, and the level of intracellular phosphorylated tau from these cultures.

We observed that antidepressants and bladder antimuscarinics were consistently cytotoxic, whereas antihistamines and antispasmodics did not show overt cytotoxicity at the times and concentrations that we tested. Some of the cytotoxic medications altered the amounts of Aβ1-42 peptides, but there were no significant differences in the intracellular ratio of phosphorylated tau/total tau between AC drug treatments. Conclusions: These results corroborate population-based studies and suggest a molecular basis for the differences in dementia risk observed according to AC class. This warrants future work examining the effect of AC medications on hiPSC-derived cells from multiple subjects and examining other molecular outcomes including synaptic function and neuroinflammation in hiPSC-based models. Highlights: Certain classes of anticholinergic (AC) medications are linked to dementia.Human-induced pluripotent stem cell (hiPSC) models are used to directly test the cytotoxicity of AC medications.AC classes that are associated with dementia are more neurotoxic.